Dietary and nutritional compositions and methods of use

ABSTRACT

A hydrated lecithin carrier vesicle composition includes lecithin and a triglyceride source or fatty acid in conditioned water. The disclosed compositions may be used for controlling appetite, weight loss, modulating effects from alcohol consumption, and/or delivering active agents to the small intestine.

CROSS-REFERENCE TO RELATED APPLICATION(S)

The present application claims priority to and the benefit of U.S.Provisional Application Serial No. 61/599,786 filed on Feb. 16, 2012,the entire contents of which are incorporated herein by reference.

FIELD

Embodiments of the present invention are directed to lecithin andtriglyceride or fatty acid carrier compositions and use of thesecompositions for improved health.

BACKGROUND

Metabolic syndrome refers to a group of risk factors that raises therisk of heart disease and other health problems, such as diabetes andstroke. The risk factors include high blood pressure, obesity, highcholesterol, and insulin resistance. In particular, a person's risk ofhaving metabolic syndrome is closely linked to the person beingoverweight or obese and/or lacking of exercise. Obesity is thus relatedto the increased prevalence of diabetes, cancer, hypertension, highcholesterol, and coronary artery disease. In addition, co-morbiditiesinvolving the central nervous, such as depression, anxiety, substanceabuse, insomnia and chronic pain may be complicated by obesity.

For both health and body image reasons, there are many individuals whowish to lose weight and/or desire to retain a lower weight after havinglost weight. In the majority of cases, weight control is simplydependent on the balance between caloric intake (food/beverage) andcaloric output (exercise). A widely pursued goal is the facile reductionof caloric intake.

SUMMARY

In some embodiments of the present invention, a composition includes astable homogenous dispersion of a vesicle and conditioned water, has amembrane and an aqueous phase, and includes lecithin, and a triglyceridesource and/or at least one fatty acid dispersed therein.

In some embodiments of the present invention, methods for decreasingappetite in a human or animal includes includes administering thecomposition to the human or animal In some embodiments, methods foraiding weight loss in a human or animal includes administering thecomposition to the human or animal

In some embodiments of the present invention, methods for increasingdelivery of an agent to the body including the circulatory system andbloodstream of a human or animal include administering the compositionto the human or animal

In some embodiments of the present invention, methods of attenuatingfacial flushing and increases in heart rate of a human or animal causedby consumption of alcohol, include administering the composition to thehuman or animal

BRIEF DESCRIPTION OF THE DRAWINGS

These and other features and advantages of the present invention will bebetter understood by reference to the following detailed descriptionwhen considered in conjunction with the accompanying drawings, in which:

FIG. 1 is a graph showing the average percent of weight change amongstall 12 volunteers for each of 14 days as indicated and described inExamples 1 and 2, according to some embodiments of the presentinvention;

FIG. 2 is a graph comparing the percent blood alcohol content (BAC) overtime (minutes) of an adult male comparing the BAC levels afterconsumption of alcohol and after consumption of a Formula composition(closed squares), a water Control composition (open diamonds), a fatControl composition (open circles), or a Retort composition (closedtriangles), as described in Example 3, according to some embodiments ofthe present invention;

FIG. 3 is a graph comparing the percent BAC over time (minutes) an adultmale, after consumption of alcohol and after consumption of acomposition of a water control (open diamonds), Formula×2 (closedsquares), or a Formula×2:OO (open circles), as described in Example 4,according to some embodiments of the present invention;

FIG. 4A is a graph of the percent of mono- and tri-unsaturation versusthe overall percent of unsaturation for the indicated triglyceridesources, as described in Example 5, according to some embodiments of thepresent invention.

FIG. 4B is an unsaturation profile showing the weight ratio (w:w) ofunsaturation from mono- and tri-unsaturated fatty acids (ODD) to thatfrom di-unsaturated acids (EVEN) as a function of the weight ratio (w:w)of the overall unsaturated to saturated fatty acids, as described inExample 5, for triglyceride sources in some embodiments of the presentinvention.

FIG. 5 is a graph of the BAC over time for compositions having “lowcitrate pH 5.4″ (open squares), “low citrate pH 4.2” (open triangles),or “high citrate pH 4.2” (closed circles), as described in Example 6,according to embodiments of the present invention.

FIG. 6A is a heart rate trace taken on an individual after consumptionof alcohol without prior consumption of a disclosed composition, asdescribed in Example 7;

FIG. 6B is a heart rate trace taken on the same individual as in FIG. 6Aafter consumption of alcohol with prior consumption of the disclosedcomposition, as described in Example 7, according to embodiments of thepresent invention.

FIG. 7A is a schematic of a face showing an image intensity lineindicating the image area that was analyzed using image software toanalyze flushing of the face, as described in Example 7, according toembodiments of the present invention;

FIG. 7B is an image intensity profile of the analyzed photo images takenalong the image line depicted in FIG. 7A of the face of the individualtested in FIGS. 6A and 6B, as described in Example 7, according toembodiments of the present invention; and

FIG. 8 is a graph showing the total elevation of eicosapentaenoic acid(EPA) and docosahexaenoic acid (DHA) in plasma over time afterconsumption of the disclosed Formula having 1.2 g of EPA/DHA (closedcircles; the 3 point moving average shown as a solid line), and acomparative omega-3 gel cap (open triangles) as described Example 8,according to embodiments of the present invention.

DETAILED DESCRIPTION

According to embodiments of the present invention, a compositionincludes a mixture of triglyceride and lecithin dispersed in an aqueousmedium. In some embodiments, the lecithin includes a hydrated lecithincarrier vesicle. As used herein, the terms “triglyceride/lecithincomposition” and “triglyceride-lecithin mixture” are usedinterchangeably and refer to a hydrated lecithin carrier vesicleincluding triglyceride and/or triglyceride hydrolysis products, andconditioned water, or the homogeneous mixture of lecithin andtriglyceride before hydration with conditioned water.

In some embodiments of the present invention, controlling appetite of ahuman or animal includes administering a triglyceride/lecithincomposition to the human or animal The method of decreasing appetitefacilitate weight loss by reducing the quantities of food the person oranimal consumes at normal meals, and reducing snacking between meals.For certain users, the compositions according to embodiments of theinvention, may provide additional benefits, including improvedself-image, and may increase the user's tolerance for alcohol or improvethe user's nutrition. As used herein, “user” refers to a person oranimal to which the disclosed composition is administered , by which themethod of weight loss or weight control or alcohol tolerance isperformed.

Embodiments of the invention relate to intermediate compositions andfinal compositions for administration to a user, and to applications ofthe compositions. The particular compositions include homogeneousmixtures of lecithin and dietary lipids, for example, triglycerides andtheir hydrolysis products, which may be prepared according to themethods described in U.S. patent application Ser. No. 13/135,057, titledLecithin Carrier Vesicles and Methods of Making the Same, filed Jun. 23,2011, the entire content of which is incorporated herein by reference.These compositions produce surprising effects on satiety, and therebyfacilitate weight loss or weight control. These compositions also havethe potential to moderate the rate and/or extent of uptake of otherco-formulated, co-ingested or subsequently ingested food and beveragecomponents. The particular triglyceride mixtures of certain embodimentsinclude a low intake of fat (approximately 2.5-5.0 grams, i.e., ½-1teaspoon) consumed prior to meals. This has surprisingly been found toproduce a sensation of satiety, and apparent moderation of caloricintake, that leads to weight loss. The onset of the effect is relativelyrapid (e.g., within 20 minutes of consumption of the composition), andlasts several hours, based on reported observations. Without being boundto a particular explanation of the phenomenon, it is plausible thatpre-emulsifying a relatively small amount of triglyceride with lecithinas disclosed herein, promotes rapid and efficient uptake of fat in thesmall intestine which in turn leads to sensations of having consumed alarge amount of fat and hence a feeling of fullness. Although thepresent disclosure may refer to certain compositions being “ingested”,it is understood that the compositions may also be “administered” incertain embodiments. As used herein, the term “ingested” refers toconsumption of a composition by a human or animal As used herein, theterm “administered” refers to providing a composition to a human oranimal for consumption.

In some embodiments, in addition to the concentrated dispersion of thelecithin-triglyceride mixture, consuming a volume of liquid thatengenders a feeling of fullness provides for additional caloric intakecontrol. A suitable volume is about 8 oz. or about 250 ml, but smalleror larger volumes can be used depending on the specific effect desired.For example, the concentrated dispersion can be diluted to the desiredtotal volume.

In other embodiments, a triglyceride/lecithin composition may help inthe metabolism of alcohol by slowing or delaying its uptake into thebloodstream. This mechanism allows for decreased blood alcohol content(BAC) and presumably lower blood levels of acetaldehyde, the initialalcohol breakdown product, leading in some cases to an increasedtolerance for alcohol. An increased tolerance for alcohol may be mostnotably useful for users having low levels of aldehyde dehydrogenase inwhich ordinarily causes users to experience facial flushing andincreased heart rate upon consumption of alcohol.

In other embodiments, a triglyceride/lecithin composition may includeadditional fatty acids. The “essential fatty acids” alpha-linoleic acidand linoleic acid are desired as they are required for biologicalprocesses, yet they are not synthesized by human, and, therefore must beconsumed. These essential fatty acids are required for the biologicalsynthesis of the omega-3 fatty acids, eicosapentaenoic acid (EPA) anddocosahexaenoic acid (DHA), which are necessary for many basic cellularfunctions, thereby providing multiple health benefits to the user. Aswould be recognized by those of ordinary skill in the art, the term“essential fatty acids” is a term of art used to identify certain fattyacids, and does not indicate that the listed materials are essential orcritical to the practiced embodiments of the present invention. In someembodiments, the triglyceride-lecithin composition includes at least onefatty acid. In some embodiments, a user's consumption of atriglyceride-lecithin composition including at least one fatty acidresults in an increase in the amount of fatty acids found in the bloodplasma of the user.

In some embodiments, the presently disclosed compositions may alsoinclude food-grade buffer ions, for example, citric acid (which is alsoa flavor agent) or phosphoric acid. There are many food acids, known asacidulants, that are commonly used in beverages and that are suitablefor use in the present compositions. Non-limiting examples of acidulantsinclude citric acid, phosphoric acid, acetic acid, lactic acid, malicacid, tartaric acid, and combinations thereof. In some situations, thecontent of lyotropic buffer ions of the acidulant may be limited whenother formulation constraints (e.g., taste and buffer capacity at aparticular pH) allow for decreasing or removing lyotropic buffer ions.In some embodiments, a triglyceride/lecithin composition includes citricacid for purposes of buffering the composition from the low pH of auser's stomach.

Common buffer systems include acceptable food acidulants and theirsalts-including both potassium and sodium. In some situations, potassiumis used rather than sodium cations to keep the sodium content low, andthe content of lyotropic ions minimized. For example, for citrate,tartrate or other polycarboxylic acid buffer anions, having an exemplarymaximum concentration is 25 mM (expressed as the combined concentrationof the corresponding acid and the anion). In another exemplaryembodiment, the concentration of the acid and anion is less than 10 mM.In yet another embodiment, the concentration of the acid and anion isless than 2.5 mM. In still another embodiment, the polyvalent anionicbuffer species are substantially absent. As used herein, the term“substantially” is used as a term of approximation and not a term ofdegree, and is intended to account for inherent deviations in a listedvalue caused by the normal uncertainty involved in measurements andcalculations. In some embodiments, the ratio of buffer to lecithin isnot less than about 0.1:1 (mole:mole). In other embodiments, the ratioof buffer to lecithin is not less than about 1:1. In other embodiments,the ratio of buffer to lecithin is about 2.5:1. In still otherembodiments, the ratio of buffer to lecithin is not less than about 5:1.

In other embodiments, the disclosed triglyceride-lecithin compositionsare stabilized with respect to microbial exposure by inclusion apreservative, such as benzoic acid/sodium benzoate or potassium sorbate,and/or adjusting the final pH of the composition to be in the “acidfood” range, i.e. at or below pH 4.5. In certain instances, an additivesuch as a polysorbate may be employed with the effect of stabilizing thecomposition to chemical and/or physical degradation or of changing theorganoleptic properties of the composition.

The compositions of certain embodiments of the present invention arepalatable and may be enjoyed as still or carbonated flavored beverages.As compounded and produced by the method described below and in U.S.patent application Ser. No. 13/135,057 (the entire content of which hasbeen incorporated herein by reference), the presently disclosedcompositions are substantially free of the taste and unpleasant oilymouthfeel associated with typical plant based oils such as corn oil.They offer the advantage of consumer acceptance, and substantiallyeliminating the reluctance to consume based on taste and mouthfeel. Theacceptable and not unpleasant mouthfeel of the disclosed compositionscan lead to better compliance with any weight control regimen involvingroutine consumption of any of the disclosed compositions.

As discussed above, compositions according to embodiments of the presentinvention include lecithin and a triglyceride source dispersed in thelecithin, as well as conditioned water. In certain embodiments of thepresent invention, the lecithin and conditioned water form a hydratedlecithin carrier vesicle (HLCV) composition including the lecithin,which can have a phosphatidylcholine content of at most about 80 w/w %and the conditioned water. The conditioned water hydrates the lecithinto form an HLCV. In some embodiments, the HLCV may have at least oneactive ingredient dispersed therein. However, in some embodiments, theHLCV composition includes alcohol which can help form HLCV dispersionsof the active ingredient and ensure proper hydration in the conditionedwater. In other embodiments, the HLCV composition further includes oneor more stabilizing agents. In some embodiments, the active ingredientis solubilized in lecithin with or without alcohol in a homogeneousliquid mixture. Other embodiments of the present invention are directedto methods of making the HLCV compositions and homogeneous mixtures.

In other embodiments of the present invention, a hydrated lecithincarrier vesicle (HLCV) composition consists essentially of a vesiclehaving a membrane and an aqueous phase, and conditioned water. In theseembodiments, the term “consists essentially of refers to the generalabsence from the composition of lecithin particles and lecithin-basedparticles (or nanoparticles) that are not vesicles, within the meaningof that term as defined below. However, these embodiments include thesame vesicles as the embodiments described above and below, and can bemade by any of the methods described below. Also, these embodiments canfurther include any of the below described active ingredients and/orother components (e.g., stabilizing agents, alcohols and/or oils).Indeed, other than generally excluding the presence in the compositionsof non-vesicle lecithin-based materials (e.g., non-vesicle lecithinparticles and nanoparticles, and/or nanocrystals of active ingredientthat are coated with non-vesicle lecithin), these embodiments may havethe same composition as the embodiments described above and below (e.g.,they may be made using the same materials and methods, and may includethe same active ingredients, and other components, such as alcohols,stabilizing agents, oils, etc.).

The use of lecithin to disperse active ingredients, according to thisdisclosure, has utility for compounds to be ingested and is also ofutility in many other areas including, without limitation, the fields ofagriculture, horticulture, nutraceuticals, pharmaceuticals (for thediagnosis, treatment and palliation of disease), cosmetics and personalcare products, fragrances and color agents, environmental remediation,inorganic and composite materials, paints and inks, catalysis, and suchother fields where a low cost natural dispersing agent is desirable. Inall embodiments of this invention, it is contemplated that other agents,including water-soluble substances, may optionally be added to thehydrated lecithin carrier vesicle dispersions to enhance theirsuitability for use in a given application, for example addition of awater-soluble anti-oxidant such as ascorbic acid to improve shelf-lifeof a nutrition product. Selection of the specific additives will beobvious to those of ordinary skill in the art.

Embodiments of this invention provide for the use of bulk food orindustrial grade lecithin to solubilize water-insoluble and partiallywater-insoluble substances in a manner that is cost-effective for broaduse in consumer products, including food, beverage and nutritionalsupplements, and in other applications where effective commercializationis dependent on the cost of raw materials that precludes the use of highPC lecithin (i.e. lecithin having more than 80 w/w %phosphatidylcholine).

As used herein, lecithin is defined as a complex mixture obtained fromanimal and plant sources by hydration of solvent-extract oils, asdefined in the Joint World Health Organization/United Nations FoodSafety Agency Evaluation Committee for Food Additives (JECFA). (Food andAgriculture Organization of the United Nations, Food and Nutrition Paper52, “Compendium of Food Additive Specifications” (FNP 52), Addendum 2(1993)), which is incorporated herein by reference in its entirety. Thiscomplex mixture comprises acetone-insoluble phosphatides includingpredominantly phosphatidylcholine, phosphatidylethanolamine, andphosphatidylinositol, as well as smaller amounts of triglycerides, fattyacids, and carbohydrates.

As used herein, vesicle is defined as a composition having amembrane-forming lipid component and an aqueous phase. In someembodiments, the membrane-forming lipid component is a phospholipidbilayer membrane.

As used herein, active ingredient refers to any compound that isselected to be and is capable of being incorporated into the vesicle.For example, in some embodiments, the active ingredient can belipophilic which includes many amphiphilic compounds, as discussedbelow. Lipophilic compounds are more soluble in fats, oils, lipids andorganic solvents such as ethanol, methanol, ethyl ether, acetone,chloroform and benzene than in water. Within their structure, lipophiliccompounds may contain hydrophilic moieties, such as the hydroxyl groupin sterols and the carboxylic acid group in long chain fatty acids. Insome embodiments, lipophilic compounds are incorporated with themembrane-forming lipid component of the vesicle. In some embodiments,lipophilic compounds have log P values in a range from about 0 to about8, where the higher log P value corresponds to increased lipophilicity.In some other embodiments, the lipophilic active ingredient has a log Pvalue range from about 2 to about 7.

As used herein, the term “lipophilic compounds” and “lipophilic activeingredient” are used interchangeably, and refer to compounds havinggreater solubility in organic solvents, fats and oils, than in water.The term “lipophilic” also encompasses many amphiphilic compounds, whichinclude compounds having both hydrophobic and hydrophilic regions.Indeed, molecules may contain water-loving (hydrophilic) moieties, suchas the hydroxyl group in sterols and the carboxylic acid group in longchain fatty acids. This is true for many (biologically) active speciesfor which embodiments of this invention provides compositions andmethods for aqueous dispersion formation. In such cases the moleculesmay also be described as amphiphilic. The methods and compositions ofcertain embodiments of this invention encompass entities that may be sodescribed and that can be dispersed in hydrated lecithin vesiclebilayers; some embodiments are shown in the examples. In general,amphiphilic molecules are arranged in both portions of the bilayer, withtheir hydrophilic portions associated with the polar surface and thehydrophobic portions directed to the acyl chains of the phospholipids inthe bilayer interior.

As used herein, dispersion refers to a lecithin-based phase generallyuniformly distributed in the bulk aqueous solution. Further, as usedherein, the dispersion is stable if it does not suffer from physicalinstability manifested by visible phase separation, such as when thevesicles aggregate and separate by precipitation or creaming (i.e.aggregates fall to the bottom or rise to the top of the mixture,respectively) or when the incorporated lipophilic materials separatefrom the vesicles and form visible aggregates. That is, in a stabledispersion of HLCV without an active ingredient, substantially all ofthe vesicles in the dispersion are distributed without visible clumping.For a stable composition including an active ingredient, in addition tothe vesicle stability discussed above, the active ingredient remainsproperly associated with the vesicles. For example, if a lipophiliccompound is incorporated in an HLCV dispersion, the hydrophobic regionsof the lipophilic compound are associated with (in contact with) thenon-polar regions of the phospholipid vesicle membrane. For acomposition including lipophilic compounds having hydrophilic moietiesincorporated in an HLCV dispersion, the hydrophilic regions of thelipophilic compounds are associated with the polar regions and thehydrophobic regions are associated with the non-polar regions of thephospholipid vesicle membrane. As such, a stable HLCV having anincorporated active ingredient also means that substantially all of theactive ingredient present in the composition is incorporatedinto/associated with the vesicle membrane. The vesicle carrier having anactive ingredient in its membrane is also referred to as a “loaded”carrier vesicle, and refers specifically to the active ingredient beingincorporated in the phospholipid membrane of the vesicle to stabilizethe compound from aggregation or degradation in the bulk aqueoussolution. Accordingly, the active ingredient incorporated in thephospholipid membrane environment, and so dispersed in an aqueousmedium, is stabilized in other environments (e.g., food, beverages,gastro-intestinal or digestive tract).

As used herein, conditioned water is defined as water that has less than100 ppm hard ions, and in some embodiments less than 60 ppm hard ions.Hard ions cause hardness in water, and the free hard ions commonly foundin water are calcium and magnesium ions. Conditioned water refers towater having a reduced level of free hard ions whether the water has areduced level without treatment (i.e. “soft” water) or if treatment isrequired. Hardness is measured by an EDTA titration method such as thatdescribed in ASTM method D1126 “Standard Test Method for Hardness inWater,” the entire content of which is incorporated herein by reference.The treatment to reduce hardness may include chelation. Naturally softwater, (i.e., water having hardness less than about 100 ppm of hardions), is considered to be conditioned water for the purposes of thisdisclosure. In some embodiments, the water is substantially free ofbuffer ions and in other embodiments, the water has been purified bydistillation, deionization, reverse osmosis or a similar technique suchthat the conductivity is less than 20 microSiemens per centimeter.Buffer ions are those that resist changes in their pH, for examplephosphate, citrate, acetate and tris(hydroxymethyl)methylamino ions.Embodiments of the present invention recognize that the quality of thewater has an effect on the final dispersion and stability of thelecithin vesicles. Compositions having unstable vesicles and/or vesicles(even if stable) having a broad or skewed size distribution can resultin cloudy (turbid) dispersions. Accordingly, though the addition orpresence of stabilizing agents is not necessary, in the absence ofstabilizing agents, the likelihood of the HLCVs to cause whitening isinversely dependent on water purity—i.e., as water purity increases, thelikelihood of whitening decreases.

Hydrated Lecithin Carrier Vesicles (HLCVs)

Embodiments of the present invention are directed to hydrated lecithincarrier vesicles in which one or more active ingredients areincorporated. The HLCVs are prepared using lecithin having a low PCcontent and conditioned water (CW). In some embodiments, a HLCV isprepared using lecithin having a triglyceride source incorporatedtherein.

Lecithin Having Low PC Content

The lecithin used to make the HLCVs has a low PC content. As usedherein, lecithin having a low PC content means a lecithin ranging fromnon-deoiled (crude) lecithin to lecithin having a phosphatidylcholinecontent of approximately 80 w/w % or less. Indeed, in some embodiments,the lecithin has a PC content of less than, but not including 80 w/w %.For example, the HLCV dispersion can be prepared from known food-gradematerials that are acceptable for consumption, including those listed asGenerally Regarded As Safe (GRAS) by the US Food and DrugAdministration. Accordingly, embodiments of the present invention havefood-grade lecithin for which the phosphatidylcholine content is fromabout 20 to about 80 w/w %. In other embodiments, the lecithin has aphosphatidylcholine content from about 20 to about 70 w/w %. In otherembodiments, the lecithin has a phosphatidylcholine content from about20 to about 60 w/w %. In other embodiments, the lecithin has aphosphatidylcholine content from about 20 to about 50 w/w %. In otherembodiments, the lecithin has a phosphatidylcholine content from about20 to about 40 w/w %. In other embodiments, the lecithin has aphosphatidylcholine content from about 20 to about 30 w/w %. In someembodiments, lecithin that has not been de-oiled is used, for which thephosphatidylcholine content is from about 20 to about 25 w/w %.

Active Ingidient

Non-limiting examples of lipophilic active ingredients include:olfactants, such as natural and synthetic fragrances and essential oils(which are described in more detail below); flavor compounds and tastemodifiers, such as natural essences and essential oils, for example fromapple, orange and lemon, (including combinations of such compounds withcarrier oils); coloring agents, such as porphyrin based macrocycles;plant oils, including olive oils, flax oils, almond oils, canola oils,and corn oils; vitamins, such as vitamins A, D, E, and K and theirpharmacologically active metabolites, salts and compounds, for examplevitamin D, vitamin E acetate and vitamin A palmitate; phytochemicals,such as plant sterols and essential oils, for example beta-sitosterol,isoflavones, curcuminoids, and polyphenolic compounds; oil soluble acidsand alcohols, such as lactylic acid and triglycerides having fattyacids, as well as essential fatty acids alone, for example linoleic andlinolenic acids, eicosapentaenoic acid (EPA) (20:5 n-3) anddocosahexaenoic acid(DHA) (22:6 n-3) and their natural sources, such asevening primrose oil, safflower oil and fish oil; drugs such ascyclosporin A, propofol, fat soluble protease inhibitor antiretroviraldrugs, antibiotics and lipophilic members of other drug classes;carotenoids, such as beta-carotene and lycopene; steroidal hormones,such as estrogens, estradiols, and cortisones; flavonoids, such asresveratrol; proteins, enzymes, coenzymes and numerous other lipophilicbiologically active compounds. It is obvious, however, to those ofordinary skill in the art, that the compounds are not limited toparticular classes of lipophilic ingredients of foods, beverages,medicines and nutritional supplements.

As used herein, an essential oil is a concentrated, hydrophobic liquidcontaining volatile aroma compounds from plants. Essential oils do notnecessarily as a group have specific chemical properties in commonbeyond conveying characteristic fragrances. They are well known fortheir use as olfactants and flavoring agents and find wide utility intraditional medicine. (Traditional medicine, as defined by the WorldHealth organization, refers to the knowledge, skills and practices basedon the theories, beliefs and experiences indigenous to differentcultures, used in the maintenance of health and in the prevention,diagnosis, improvement or treatment of physical and mental illness).

Alcohol

In some embodiments, the HLCV composition includes alcohol. In someembodiments, alcohol is added to the conditioned water for hydration ofthe lecithin to form the HLCVs. In other embodiments, if the activeingredient is not easily solubilized in the lecithin composition, theaddition of alcohol can improve solubilization of the active ingredientin the homogeneous liquid mixture. According to embodiments of thepresent invention, the alcohol is a short chain alcohol. Examples ofshort chain alcohols include methanol, ethanol, isomers of propanol, andisomers of butanol. The amount of alcohol needed to facilitatesolubilizing the active ingredient will vary depending on the type ofalcohol and the particular active ingredient, and can be determinedempirically by a person having ordinary skill in the art.

In some embodiments, the alcohol added to help dissolve the activeingredient in the lecithin to form a homogenous liquid mixture, isprovided in a range from about 5 to about 50% alcohol by weight relativeto the combined weight of the lecithin and the active ingredient. Theaddition of alcohol to the lecithin and active ingredient compositionmay be with or without heating, and with or without the addition of oil,as discussed herein.

In some embodiments, alcohol is added to the conditioned water for thehydration of lecithin. In some embodiments, the additional alcohol is analiphatic short chain alcohol (e.g., methanol, ethanol, propanol, orbutanol). The amount of alcohol can vary and will depend on theproperties of the active ingredient(s). For example, for the hydrationof lecithin, up to a total of 40% v/v of an alcohol can be present inthe HLCV composition.

In some embodiments, the dispersion may be dried by standard industrialmethods for example to a powder, granule or cake form.

Stabilizing Agents

In other embodiments of the invention, the HLCV compositions furtherinclude at least one stabilizing agent. Non-limiting examples ofstabilizing agents include polysorbate (polyoxyethylene sorbitanmonoesters), polyoxyethylene alkyl ethers (PAEs), and the like. Theaddition of a stabilizing agent is optional and will generally depend onthe properties of the active ingredient(s) to be dispersed in the HLCVs.For some applications, addition of a polysorbate or PAE may increasestability. As such, the need for polysorbate or PAEs can be determinedempirically by those of ordinary skill in the art.

As used herein, the term polysorbates includes the class of emulsifierswhich are oily liquids derived from polyoxyethylene derivatized sorbitan(a derivative of sorbitol) monoesterified with fatty acids. The PAEclass of molecules is suitable for use in applications not involvingingestion of the HLCVs. It is readily apparent to those of ordinaryskill in the art that, for applications not involving ingestion, asuitable PAE may be substituted for polysorbate in the methods andcompositions described herein that include and/or employ polysorbates.

The polysorbate-containing HLCVs of embodiments of the present inventiondo not have a detectable bitter taste and are physically stable todilution, pasteurization and storage in water, many juices and otherbeverages, as demonstrated by retention of clarity. The followingpolysorbates are non-limiting examples that can be used:polyoxyethylene(20) sorbitan monooleate, polyoxyethylene(20) sorbitanmonolaurate, polyoxyethylene(20) monopalmitate, and monostearate. Insome embodiments, polyoxyethylene(20) sorbitan monooleate (i.e.,polysorbate 80), or polyoxyethylene(20) sorbitan monolaurate are used.An effective amount of polysorbate can be determined using knownmethods. In some embodiments, for example, polysorbate is used at amolar ratio of polysorbate to lecithin of between about 1:3 and about1:20. In other embodiments, polysorbate is used at a molar ratio ofbetween about 1:5 and 1:10. In other embodiments, polysorbate is used ata molar ratio of between about 1:7 and 1:9. For the purpose ofdetermining the molar ratio, the molecular weight of the lecithin is tobe assumed to be 800.

Methods of Preparing HLCV

Embodiments of the present invention are directed to methods ofpreparing hydrated lecithin carrier vesicles (HLCVs). In someembodiments, HLCVs with at least one active ingredient loaded thereinare prepared without the use of any organic solvents, alcohols orotherwise. However, in some embodiments, alcohols may be used tofacilitate making the HLCVs although other/additional organic solventsare not required or used. In some embodiments of the present invention,a method of forming an HLCV composition includes hydrating andprocessing lecithin having a low PC content in conditioned waterfollowed by the addition of at least one active ingredient. In otherembodiments of the present invention, the active ingredient may be mixedwith low PC content lecithin and an alcohol, together with minimalwater, to form a homogenous liquid phase (without forming vesicles),followed by hydration and processing which forms dispersed vesicles. Inother aspects, methods of forming HLCV compositions having an activeingredient dispersed therein include using lecithin having a high PCcontent (i.e., greater than 80 w/w % phosphatidylcholine) in conditionedwater.

Hydration of Lecithin

In some embodiments, lecithin having a low phosphatidylcholine contentis hydrated upon exposure to conditioned water to form hydrated lecithincarrier vesicles dispersed in CW. In some embodiments of the invention,the lecithin is hydrated with enough conditioned water to effectivelyperform a processing step (e.g. homogenization, sonication,microfluidization, high shear mixing, etc.). Indeed, the HLCVdispersions contain, by weight, at least as much conditioned water aslecithin, (i.e. a ratio of CW to lecithin of at least 1:1), prior to anydrying or further compounding steps. In some embodiments, for example,lecithin may be hydrated with 3 parts water to 1 part lecithin (byweight). In other embodiments, lecithin may be hydrated with up to 4parts water to 1 part lecithin, or 5 parts water to 1 part lecithin, byweight. In other embodiments, lecithin may be hydrated with greater than5 parts water to 1 part lecithin. In these embodiments, the relativeamounts of CW and lecithin are relative to the lecithin alone.

In other embodiments, lecithin is hydrated in the presence of at leastone active ingredient. In these embodiments, the ratio of lecithin toactive ingredient is at least 1:1 and may, in general, be up to about5:1 by weight. However, there is no particular upper limit to this ratioother than imposed by commercial or practical processing constraintsobvious to those of ordinary skill in the art. In these embodiments, theconditioned water is provided at a ratio of CW to the sum of lecithinand active ingredient ranging from about 3:1 to about 5:1, by weight.This is necessary as the active ingredient can be provided up to about a1:1 ratio with the lecithin. For example, when the total weight oflecithin and active ingredient is 200 to 250 mg (lecithin +activeingredient), the amount of CW could be 1 ml (1000 mg). It is apparent tothose of ordinary skill in the art that the amount of conditioned waterwith respect to the lecithin or lecithin and active ingredient, is, ingeneral, only limited by the desired concentration of HLCV compositionand active ingredient with respect to any further production ormanufacturing steps for the final desired application of thecomposition.

Loading of Active Ingredient in HLCVs

In some embodiments, HLCV compositions are prepared, (i.e., lecithin ishydrated and then processed) to form dispersed vesicles prior to theaddition of at least one active ingredient. These methods of formingHLCVs prior to loading the active ingredient(s) are most effective whenthe active ingredient is a liquid (e.g., is in liquid form at atemperatures up to the boiling point of the conditioned water or theboiling point of the conditioned water and alcohol mixture), so that theactive ingredient is easily solubilized in the hydrated lecithin vesiclecomposition. These methods of adding the active ingredient afterprocessing (i.e., to pre-formed vesicles) are particularly suitable forsuch ingredients as essential oils, lipophilic flavor compounds, andflavor compound mixtures having lipophilic components. This method ismost effective for HLCVs that have been processed (e.g. byhomogenization or high shear mixing) to form UVs prior to loading.Accordingly, if the active ingredient can be incorporated in thehydrated lecithin composition, then the active ingredient can be addedto “pre-formed” lecithin vesicles. As discussed above, solubility of theactive ingredients may require the addition of alcohol, heating, or anycombination of these. It is apparent to those of ordinary skill in theart that an active ingredient having a low solubility, if added in asmall amount would slowly be incorporated in the vesicle compositionover time. It is also known to those of ordinary skill in the art thatthe extent of incorporation in the dispersed HLCVs is dependent on boththe rate at which the active dissolves in the aqueous phase and time.Without the aid of alcohol, or heating, an active ingredient having alog Kow (i.e., an octanol:water partition coefficient) of less thanabout 4.5, will not likely be incorporated within a reasonable amount oftime. However, active ingredients having a log Kow of 4.5 or greatercould be incorporated more rapidly. Solubility of such activeingredients, including as enhanced by heat and/or alcohol, can bedetermined empirically by those of ordinary skill in the art.

A stabilizing agent can be added to the lecithin composition prior to orafter processing. In some embodiments, a stabilizing agent is added tothe HLCV composition after processing. In other embodiments, a mixtureof lecithin and a stabilizing agent is hydrated in CW prior toprocessing.

Following addition of the active ingredient to the HLCVs, the mixture isprocessed by high shear mixing or homogenization to form a dispersedcomposition of HLCVs having an active ingredient incorporated therein.

Transparency

In some embodiments, the size distribution of the lecithin carrierdispersion can be manipulated such that the dispersion is essentiallyoptically clear (i.e. transparent). For the purpose of describingembodiments of the invention herein, the mean diameter of dispersionparticles and structures in the submicron range (<1 μm) is defined asthe volume weighted mean diameter, generally of a unimodal distributionof sizes. The volume weighted mean diameter of the vesicles can bedetermined by any known technique. For example, the volume weighted meandiameter is determined using electron microscopy or dynamic lightscattering. Upon determining the mean vesicle size, the vesicles can bereduced in size using standard methods well known in the art, includingwithout limitation: sonication, microfluidization and high pressurehomogenization.

In some embodiments, a lecithin carrier vesicle having an activeingredient therein and prepared by a method of according to embodimentsof the present invention, remains clear (or, transparent) in dispersion.Clarity refers to transparency rather than translucency. Thistransparency is achieved by producing a dispersion wherein the meandiameter of the particles is about 0.12 μm or less, preferably less than0.10 μm, and more preferably less than 0.08 μm. Additionally, thedistribution of sizes includes few particles of larger diameters thatcause cloudiness, which may manifest as whitening. For the purpose ofdescribing certain embodiments of this invention, the presence of suchlarger particles may be quantitated by the cloudiness or haziness,hereafter referred to as turbidity. Transparent dispersions are thosewith low turbidity. The quantitation of such turbidity may be performed,for example, using a nephelometer. Turbidity of dispersions may beexpressed relative to standards of known turbidity. The turbidity causedby scattering of light by submicroscopic particles, even those withdiameters significantly smaller than the wavelength of the light, is acomplicated function of many variables including both the particle sizeand the wavelength. In general, the presence of larger particles, i.e.those that cause turbidity (whitening, cloudiness, haziness), isrevealed by scattering at longer wavelengths. This scattering of lightresults in the observed turbidity (i.e., lack of clarity) of aqueousdispersions. A quantitative measure of relative turbidity is therelative absorbance at 800, 860 and/or 900 nm as measured using aconventional UV/visible spectrometer. Turbidity caused by instability ofthe dispersions is thus readily quantitated by spectrophotometricmethods in the desired range.

While HLCV compositions with or without dispersed active ingredients maydesirably be transparent or nearly so, transparency is not a requirementof any embodiment of the present invention. For example, if thecomposition is intended to be added to a food product, its clarity insolution is typically not relevant, and therefore it may not benecessary to reduce the vesicle size. However, if the composition isintended to be added to a transparent or semi-transparent drink, forexample, the cloudiness or turbidity may desirably be adjusted to meetconsumer expectations.

Homogeneous Liquid Mixture

In some embodiments, the active ingredient is added to the lecithinprior to hydration. In these embodiments, the active ingredient may bedissolved at room temperature in the lecithin based mixture, which mayalso include alcohol and may also include a minimal amount ofconditioned water and/or an oil. In some embodiments, the weight amountof lecithin in the homogenous liquid mixture is greater than any othersingle component of the homogenous liquid mixture. That is, while thelecithin may not be more abundant than all other components combined, itis provided in an amount that is more than any other single component.In this way, lecithin may be used as a solvent for the homogenous liquidmixture. Some active ingredients may more readily solubilize withheating. In some embodiments, therefore, the active ingredient is mixedwith lecithin, and may include alcohol, a minimal amount of alcohol,oil, and may be mixed at an elevated temperature. For example, theheating temperature is selected from a range of about 60° C. to about80° C. The desired temperature may be determined by one of ordinaryskill in the art with consideration of the properties of the activeingredient and the components of the composition. For example, theheating temperature should not exceed the boiling point of thecomposition which is dictated by the various components of thecomposition. As would be understood by those of ordinary skill in theart, the heating temperature should not exceed the boiling point of thecomponent of the composition which has the lowest boiling point. Forexample, if alcohol is present in the lecithin composition, then thehighest desired heating temperature should not exceed the boiling pointof the alcohol (which in general will be the component with the lowestboiling point). In some embodiments, lecithin and at least one activeingredient are first dissolved in a homogenous liquid mixture prior tovesicle formation.

By way of example, plant phytosterols have a melting temperature above100° C. (e.g. beta-sitosterol has T_(mp) of 136 to 140° C.), andtherefore, plant phytosterols are not effectively incorporated into theHLCV composition after the vesicles are formed. Accordingly, in someembodiments of the present invention, a composition having at least oneactive ingredient dispersed therein, is prepared by first dissolving theactive ingredient together with lecithin to form a single phasehomogenous liquid mixture. In some embodiments, alcohol is added to helpsolubilize the active ingredient in the lecithin. In some embodiments,up to about 50% alcohol (by weight with respect to lecithin) is added tothe lecithin and active ingredient mixture. As discussed, in someembodiments, a minimal amount of conditioned water may be added to aidin the solubilization of the active ingredient in the lecithin andalcohol mixture. For example, no more than 10% by weight (w/w)conditioned water relative to the weight of lecithin may be added. It isapparent to those of ordinary skill in the art that an excess of waterwill prevent the formation of a single phase. To further promote theformation of a homogeneous liquid mixture with the lecithin, the activeingredient may first be dissolved in an oil (with heating if necessary).

In some embodiments, the active ingredient may first be dissolved in anoil in order to facilitate solubilization in the lecithin to form thehomogenous liquid mixture. For example, an active ingredient may firstbe dissolved in a non-polar, hydrophobic carrier substance, such as anatural oil, and then mixed with the HLCV composition. Dissolution ofthe active ingredient in oil may also be combined with heating and/orthe addition of alcohol. Examples of an oil include extractedtriglyceride seed oils from plants, such as soy, corn, olive, sunflower,canola, olive. Oils also include animal oils such as fish or krill, aswell as essential oils. Essential oils include, without limitation, oilsof: citronella, clove leaf, eucalyptus, grapefruit, lemon, lime, menthaarvensis/mint, orange, oregano, peppermint, spearmint, star anise,tangerine, tea tree, thyme and wintergreen, and the embodiments includethe use of the primary chemical components of these oils, such asthymol, carvacrol, limonene, menthol, carvone, methyl salicylate,cineole, citranal, pinene, and terpinen-4-ol.

The homogeneous liquid mixture is then hydrated with mixing in CW toform vesicles. In some embodiments, a short chain alcohol is added tothe CW, i.e., if the short chain alcohol is not already present in asufficient amount in the lecithin containing mixture. A sufficientamount of short chain alcohol is no less than that which provides afinal lecithin hydrating solution concentration of at least about 5 v/v% alcohol, and no more than about 40 v/v %. In some embodiments, thefinal lecithin hydrating solution concentration of alcohol is from about20% v/v to about 30% v/v. The lecithin hydration is performed at atemperature that maintains the homogeneous liquid mixture with lecithinin a fluid state.

After formation of the HLCVs by hydration, the HLCVs are processed byhomogenization or high shear mixing to form a dispersion of the activeingredient incorporated in the HLCV composition.

HLCVs from Lecithin Having a High PC Content

In further embodiments of the invention, a method of producing an HLCVcomposition uses lecithin having a high PC content (i.e. lecithin havinga phosphatidylcholine content of more than 80% w/w). In this method,high PC content lecithin (or alternatively, substantially purephosphatidylcholine) is mixed with an active ingredient following one ofthe methods disclosed herein for solubilization of active ingredients inlow PC content lecithin. The methods and intermediate compositionsdescribed herein for adding an active ingredient after hydration andprocessing, or by forming a homogenous liquid mixture prior to hydrationand processing, are also applicable to the preparation of HLCVs usinghigh PC content lecithin. Such HLCVs are suitable for uses inpharmaceutical applications. Indeed, in these embodiments, the lecithinhas a higher PC content such that it is acceptable for pharmaceuticaluse. For example, in these embodiments, the HLCVs have 90 w/w % orgreater PC by weight for an inhaled or injectable product.

Other purified phospholipids may be added as required for the desired invivo performance of the formulation. In some embodiments, apharmaceutically acceptable formulation of propofol for parenteral usemay be made by hydrating an alcoholic mixture of phosphatidylcholine andphosphatidylglycerol in conditioned water, followed by homogenizationwith a high pressure homogenizer, and then incubation with propofol.

Optionally, a pharmaceutically acceptable stabilizing agent, such aspolysorbate, may be added during hydration or after processing. Theorganic solvent-free processing method disclosed herein for lecithin isalso applicable for pharmaceutically acceptable phosphatidylcholine. Thealternative method, based on a homogeneous liquid mixture of lecithinand other ingredients, may be used with those pharmaceutically activeingredients that are soluble in the phosphatidylcholine-alcohol mixturescorresponding to those described with respect to the low PC contentlecithin embodiments, with the addition of a small amount of conditionedwater (up to 10% w/w relative to phospholipids) as required to generatea homogeneous liquid mixture. As described herein, the active ingredientmay first be dissolved, with heating if necessary, in a pharmaceuticallyacceptable oil, such as a triglyceride ester of fatty acids (wherein thefatty acids may be the same or mixed).

Further Processing Purification

Following formation of the HLCVs the composition can be furtherprocessed as desired. For example, to reduce the vesicle size, thedispersion can be subjected to high shear mixing or high-pressurehomogenization. The energy required for size reduction is reduced by thepresence of alcohol, compared to the corresponding size reductionprocess performed, if feasible, on the same components in the absence ofalcohol. The lower energy processing is of commercial benefit resultingin lower process energy costs and the ability to use a wider range ofprocessing equipment. For example, with alcohol present, a greaterdegree of size reduction can be achieved for a given energy input; insome cases this enables production of an optically clear presentation ofHLCVs whereas such optical clarity may not be achievable in the absenceof the alcohol.

The HLCV compositions as disclosed herein can be dried to a solid form,for example to a powder, flake or cake, by any standard industrialdrying method, such as spray drying or freeze drying, and alternativelyor subsequently incorporated into a paste or cream. Additional furtherprocessing steps may include: adjusting the pH of the composition,addition of preservatives or antimicrobial agents, or the addition offlavors to enhance the taste of the composition.

In some embodiments, it may be advantageous to blend hydratedtriglyceride-lecithin dispersions having different entrappedcompositions, some of which may be the exemplary compositions asdescribed above, in order to obtain a combination of immediate anddelayed action or other desirable properties.

All the above compositions and blends may be prepared with or withoutother agents such as proteins, peptides, carbohydrates, fiber, dietarysupplements, drugs or other active agents.

Applications

The HLCV dispersions according to embodiments of the present inventionare essentially free of non-dispersed active ingredients (i.e., oncedispersed in the HLCV composition, the active ingredients remainsubstantially dispersed and do not precipitate out of the dispersion toany significant degree). In some embodiments, the lecithin vesiclecompositions are distinct from nanoemulsions and from dispersions ofnon-bilayer solid nanoparticles stabilized by a surface active agent(such as lecithin).

The compositions, intermediate solutions, and methods for production, ofcertain embodiments of this invention provide for aqueous baseddispersions of water-insoluble materials using relatively inexpensivefood-grade lecithins, specifically lecithin having a PC content of lessthan about 80% by weight.

Though not limited to any applications, the HLCVs according to certainembodiments of the present invention may be used to make substantiallyclear aqueous dispersions of fat-soluble active ingredients that may beused in beverages or nutritional supplements, as the dispersions arephysically stable to dilution, pasteurization and storage in water,juices and other beverages. The fat-soluble ingredients can includeantioxidants (for example, vitamin E). The dispersion can beconcentrated and dried to a powder and rehydrated as required by thedesired application. The compositions and methods of embodiments of theinvention also disclose use of food grade materials, for example, thosethat have already been qualified in an application as Generally RegardedAs Safe by the US Food and Drug Administration.

The HLCV compositions of certain embodiments of this invention can beprocessed using conventional equipment that is widely employed in thefood and beverage industry. The components of the hydrated lecithincarrier vesicles are relatively inexpensive. In addition, the loading ofthe food/beverage/nutritional supplement ingredient into the carrier canbe elevated to levels that yield cost effective formulations for use inrelevant consumer and other products.

The HLCV dispersions of certain embodiments of the present inventioneffectively behave as true solutions and may be, or may be employed inthe preparation of, products that are to be consumed orally or otherwiseintroduced into the oral cavity. A particular benefit of some of thecompositions of embodiments of this invention is that they provideaqueous dispersions that are essentially optically clear as used infinal products, and maintain that clarity with storage, with addition tosome juices and other beverages, and with exposure to high temperature,as during pasteurization. In some embodiments, the lecithin-based matrixalso provides enhanced chemical stability of the water-insolublematerials, e.g., resistance to oxidation, and can inhibit undesirableodors and taste, and poor mouth feel of these materials. Certain lipidsare themselves considered to be food or nutritional supplementingredients of choice, for example phosphatidylcholine and, especially,lipids derived from marine organisms, such as krill. It is clear thatthe HLCVs, intermediates, and methods of preparation described herein,may optionally employ these lipids.

Specific mixtures of triglycerides, and combinations thereof with otheradditives including, protein, hydrolyzed protein, peptides, enzymes,carbohydrates, artificial sweeteners etc are particularly beneficial forcertain medical conditions. These compositions may be augmented withother dietary supplements in order to achieve a desired health benefit.With respect to satiety, in combination with other agents known toproduce satiety, the present compositions can produce a surprisinglysynergistic effect, e.g. with the incorporation of a relatively smallamount of partially hydrolyzed guar gum. For the goal of weight control,a composition with a low calorie artificial sweetener rather thansucrose, high fructose corn syrup or other natural sweetener ispreferable. Similarly, for such an application, it is desirable tominimize the calories from fat in the composition itself by minimizingthe total amount of triglyceride while retaining the desired satietyeffect. In certain instances, particularly to improve the nutritionuptake for persons in whom such uptake is impaired, for example byanatomical, physiological or digestive tolerance issues, a highercontent of triglyceride—and other components—may be desired.

While the triglyceride-lecithin compositions of certain embodiments ofthe invention can be prepared from a wide range of triglycerides, suchas natural oils, an average composition of triglyceride as defined bythe acyl chain profile (i.e., the content of mono-unsaturated fattyacid, di-unsaturated fatty acid and polyunsaturated fatty acids relativeto saturated fatty acids) includes an overall ratio of unsaturated tosaturated fatty acids of at least 4:1. In some embodiments, the(monounsaturated) oleic and (tri-unsaturated) alpha-linolenic fattyacids relative to (di-unsaturated) fatty acids in the triglyceride ofthe disclosed composition is at least 1:1. In some embodiments, theaverage oleic acid content of the triglyceride in thetriglyceride-lecithin compositions is at least 40% by weight of all thefatty acids. Examples include mixtures of corn oil with olive oil andwith canola oil.

In users having cardiovascular risks, triglyceride-lecithin compositionswithout any fatty acid chains less than C14 (14 carbons in length) andwithout any fully saturated carbon chains may be desired, as these areconsidered to be possibly harmful to cardiovascular health irrespectiveof their ability to produce satiety in users. In yet other applications,the presence of these particular short and/or fully saturated acylchains may be advantageous.

In some embodiments, the triglyceride-lecithin composition hasconjugated linoleic acid substituted for oleic and/or linoleic acid.

As discussed herein, hydrolysis products of triglycerides may also beincorporated in the compositions of certain embodiments of the presentinvention at levels that do not destabilize the overall composition inthe stomach so as to cause loss of activity. Such hydrolysis productsinclude free fatty acids and mono- and di-acylglycerides. However, fullysaturated and trans-unsaturated fatty acids, free or as glyceride acylchains, are in some instances less desirable than cis-monounsaturatedand polyunsaturated fatty acids with chain lengths between 14 and 18carbons.

Incorporation of active substances in the disclosedtriglyceride-lecithin mixtures is also contemplated, including when atherapeutic effect is desired. For example, fat soluble vitamins (suchas vitamins A, D, E and K), essential fatty acids (such as EPA and DHA),esters or triglycerides, and lipophilic drug substances, are suitablefor inclusion in the lecithin:triglyceride mixtures of embodiments ofthe present invention. This latter category includes the water insolubleactive moieties of drugs wherein solubility and bioavailability haveheretofore been achieved by formation of salts or derivatives, withhydrophilic counter-ions or non-active functional groups, respectively.Equally, water-soluble materials can be dissolved within the aqueousphase of the compositions for co-delivery. Particular triglyceridecompositions will enhance particular lipid soluble active uptake.

Without being bound to a particular theory for the basis of theactivity, the present compositions are believed to enable rapid andhighly efficient enzymatic hydrolysis of triglycerides in the duodenumby pancreatic enzymes. Compositions of the present invention provide forpresentation of the triglyceride ester linkages homogeneously dispersedwithin a phospholipid matrix. This presentation occurs at thephospholipid water interface, and possibly with endogenous bile saltsfrom the gall bladder, thereby possibly mimicking the environment thatis normally produced with bicarbonate, phospholipid, and bile salts.Transport of the active ingredients into the bloodstream occurs bynormal mechanisms and yields more rapid and/or extensive bioavailabilitythan the same molecules not formulated in the HLCVs.

For triglyceride fats, duodenal enzymatic hydrolysis yields free fattyacids and monoacyl glycerols that are taken up by cells lining the smallintestine (enterocytes). For medium and long chain fatty acids, thesemolecules are taken up from micelles and liposomes are then repackagedintracellularly as chylomicrons for delivery via interstitial fluid andthe lymph to the bloodstream. The hydrolysis products, recognized asindicative of fat consumption, trigger release of biochemical factors aspart of feedback loops. For example, the hormone, cholecystokinin, isreleased which triggers a physiological response—closing of the pyloricsphincter—as well as a brain response to reduce the impulse to eat. Whenthe pyloric sphincter is closed, the stomach is more likely to feelfull, especially if there is additional food or beverage intake. Thereare many other biochemical factors involved in food intake control loopsand the compositions of this invention may interact with some or all ofthese.

Lipophilic active agents may be formulated with triglycerides that yieldshorter chain and/or saturated fatty acids and monoacylglycerols onhydrolysis. These triglyceride hydrolysis products are often taken up byan alternative mechanism not involving liposomal and micellar molecularaggregates but diffusion of individual molecules. As such, entry intothe bloodstream that occurs via the portal vein with subsequent directtransit to the liver. In other words, the higher aqueous solubility ofthese hydrolysis products means that they do not need to remainassociated with the supramolecular aggregates in order to remaindispersed. That is, the triglyceride hydrolysis products can diffuse asindividual molecules to the enterocyte surface and then are processeddifferently (i.e. not processed via the chylomicronreassembly/repackaging) ending up in the portal vein which feedsdirectly to the liver. Co-formulation of lipophilic active agents withshorter chain and/or saturated lipids provides an alternative way toenhance their bioavailability, particularly for those with higheraqueous solubility. The particular combinations of triglycerides,lecithin and active agents that are effective can be readily determinedby one having ordinary skill in the art. Entrapment of water solubleagents in the aqueous compartment of the HLCVs, produced from theshorter chain/saturated lipids, provides a method of delivering theseagents—protected from the rigors of the stomach and in highly dispersedform—to the duodenum for facile release, with resulting improvedbioavailability compared to an active agent that is not entrapped in anHLCV. According to embodiments of the present invention, water solubleagents include known appetite suppressants. Non-limiting examples ofknown water soluble appetite suppressants include soluble fibers andphytochemicals.

The following Examples are presented for illustrative purposes only, anddo not limit the scope or content of the present application.

EXAMPLES Example 1 Flavored Triglyceride-Lecithin Composition.

A composition of 300 mL corn oil, 300 mL olive oil and 800 g of lecithinwith 75 mL 95% (v/v) ethanol and 2.5 mL lemon oil was prepared in 6liters (L) conditioned water according to the method outlined in U.S.patent application Ser. No. 13/135,057, with homogenization atapproximately 60° C. and a pressure of approximately 650 bar. Of theresulting 8 L of dispersion of triglycerides, a 4 L aliquot was mixedwith 2 L of an acidulant solution containing 105 g/L citric acid, 87.5g/L sodium citrate, 175 g/L sucrose, 1.75 g/L sodium benzoate and 35 g/Lpartially hydrolyzed guar gum. To this mixture was added 11.5 L purifiedwater, 10 mL lemon extract, 4 mL strawberry flavoring, and 7 mL 25%(w/v) sucralose solution. Final pH was less than 4.5. The volumeweighted mean diameter of the dispersion, as measured by the controlledreference method of dynamic light scattering, was about 0.15 micron.Consumption of 250 ml of the final dilution of the triglyceridecomposition induced a feeling of stomach fullness and reduced appetite.A control preparation, comprising the same amount of triglyceride per250 ml shaken in sugar water, without lecithin, did not induce the sameeffects.

Example 2 Satiety and Weight Loss Study with Triglyceride Composition.

A cohort of 12 volunteers, 7 male and 5 female, having an age range of14 to 72 years, initial weight 61 kg to 130 kg, Body Mass Index (ameasure of body fat) 23.0 to 34.9, and body surface area from 1.73 to2.39 square meters, were assigned to one or two daily servings oftriglyceride formulation prepared as outlined in Example 1. Participantswere instructed to consume a serving of the formulation approximately 60minutes before dinner (and for the two daily serving group also aboutone hour before lunch). Participants recorded their morning weight dailyand their perceived hunger before each suppressant serving andimmediately before the corresponding meal. Using a standard VisualAnalog Scale—a 100 mm long horizontal straight line with extremesdesignated “not at all hungry” (left) and “extremely hungry”(right)—hunger level was recorded by making a mark crossing the scale.Measuring the position of the mark relative to the left hand end (“notat all hungry”) was used to quantitate appetite. While inter-participantperception of hunger on the scale was unknown, the change in theappetite value for a given participant was presumed indicative ofappetite change. Results for consumption of the formulation for 14 daysare shown in FIG. 1 (average weight change as a percent of startingweight) and Table 1.

TABLE 1 # observations wt. change weight change vs day 1 possiblerecorded gain zero loss “controlled*” All participants (n = 12) 156 13115 9 107 116 89% *= unchanged or weight loss HUNGER VAS Scale Change inhunger: pre-supplement to before meal (as mm reduction) Lunch Dinner Allmeals All participants (n = 12) mean std.dev. mean std.dev. meanstd.dev. 6.4 4.9 1 serving daily 7.3 3.0 2 servings daily 7.0 5.8 4.95.4 all participants

Example 3 Alcohol Uptake Inhibition

It is well established that consumption of fat results in activation ofa feedback loop of which one component is closing the pyloric sphincter,the valve at the lower end of the stomach. If this valve is closed whenan alcoholic beverage, such as beer, is consumed, uptake of alcohol intothe bloodstream is inhibited. In contrast, alcohol drunk on an emptystomach is rapidly absorbed and “goes straight to the head.” Theseeffects occur because alcohol uptake in the duodenum, (immediately belowthe pyloric sphincter) occurs quickly, whereas the diffusion of alcoholfrom the stomach into the bloodstream is slow. In most cases, 20% of thealcohol in a drink is absorbed through the stomach and 80% through thesmall intestine. For compositions according to embodiments of thepresent invention, the relative effects on the fat intake feedback loopmay therefore be assessed using blood alcohol content (BAC)measurements, which may be obtained using a breathalyzer device. Theresults of this study are shown in FIG. 2. BAC with and without priorconsumption of a particular composition indicates the relative extent towhich the feedback loop has been activated.

Using a hand-held Blood Alcohol Content (BAC) meter, exhaled breathanalysis was used to determine BAC for an adult male. Levels weredetermined before consuming alcoholic beverages and at intervals up to90 minutes after. In the “water” control, breath analysis was taken 15minutes after consumption of 250 ml of water over a period of less thantwo minutes. Then either one or two units of alcohol (one unit is a 12oz./300 ml beer with 4.5 vol. % alcohol) was consumed over a 15-minuteinterval, the end of which was set as t=0. BAC measurements were takenfollowing rinsing of the mouth with water and a five minute delay inorder to minimize interference from any residual alcohol in the oralcavity. For test experiments, the test article (“Formula”) was consumedover a period of less than two minutes commencing 15 minutes before thestart of alcoholic beverage consumption. FIG. 2 shows results forconsumption of two units of alcohol. The control data represent the meanof two determinations. The FORMULA was 250 ml of a triglycerideformulation prepared by the method described in Example 1 and containing1.25 g corn oil, 1.25 g canola oil and 3.75 g lecithin in HLCVs—data arethe mean of duplicate studies. A further “fat” control was measured.This “fat” control included a shaken mixture of the same components asin the test FORMULA but without lecithin, and was consumed prior to thealcoholic beverage. In this lipid (“fat”) control, the amount oftriglyceride was increased to compensate for the fat content of themissing lecithin. In this case, alcohol uptake was not moderated by the“fat” control. In addition to the reduction in the BAC peak and areaunder the curve, the triglyceride-lecithin compositions induced afeeling of stomach fullness that caused significant discomfort as thesecond 12 oz. beer was consumed (a discomfort not sensed if triglyceridewas not consumed). FIG. 2 also illustrates a “Retort” control to measurethe effect of autoclaving a formulation of this invention on its abilityto modify alcohol uptake. The BAC profile for autoclaved materialclosely resembles that for the control tests. This result is presumed toindicate that the alteration of the chemical and physical structure ofthe hydrated lecithin carrier vesicles, induced by the extremeconditions of autoclaving, alters their physiological processing afteringestion.

Example 4 Alternative Formula for Inhibiting Alcohol Uptake

FIG. 3 shows the results of a similar study in which a single unit ofalcohol was consumed. The test formula (FORMULA×2; dotted line throughdark squares) was prepared as described in Example 3, but at twice theamount of the lecithin triglyceride mixture. An alternative test formulawas prepared using olive oil in place of canola oil, also at twice theamount of lipids (FORMULA×2: OO; detached line through open circles).The Avg Control is the Water control as performed in Example 3. TheLOD/LOQ shows the level of detection (LOD) over the level ofquantification (LOQ) for this BAC assay. Relative to the two units ofalcohol example, less stomach discomfort was experienced, but fullnesswas sensed with the triglyceride preparations. Results shown in FIG. 3(the average of duplicate experiments) demonstrate the reduction ofblood alcohol levels with the test formulas. For the olive oilformulation, an improved effect is found with the rate of uptakeessentially slowed to match the rate of metabolism of the alcohol in thebloodstream: the BAC remains at or close to the limit of detection ofthe BAC assay. The breathalyzer instrument used registers zero for anyBAC at or below 0.008%—conservatively, the figures show such “zero”results as 0.008%, the limit of detection/quantitation, although thetrue BAC may actually be lower. Various combinations of triglycerides(and components) with lecithin were tested for their ability to modulateBAC: results are summarized in Table 2 below. The effect of buffer isconsidered in Example 4, but a pairwise comparison shows that peak BAClevels are delayed and or/reduced more, relative to the control, forformulations with a greater degree of mono- and tri-unsaturation(averaged over all triglyceride components).

TABLE 2 COMPOSITION QTY. VOL. PEAK BAC PEAK TIME control (water) — 250ml 0.025%  5 min corn oil:palmitic acid 5 g 200 ml 0.018% 20 min(100:2.5) corn oil:canola oil:palmitic 5 g 200 ml 0.018% 25 min acid(50:50:2.5) corn oil:canola oil (50:50) 5 g 250 ml 0.012% 20 minbuffered corn oil:olive oil (50:50) 5 g 250 ml 0.009% 40 min buffered

Example 5 Bent Chain Acyl Groups for Enhanced Fat Intake Signaling

Without being bound by a particular theory for the mechanism of action,it is proposed that the presence of “bent chain” acyl groups, such asoleic and alpha-linolenic acids, either engender sufficient disorder inthe lipid bilayer structures of embodiments of the invention forenzymatic hydrolysis to be especially well facilitated and/or providefor enhanced fat intake signaling upon uptake by enterocytes. Canola oiland olive oil are examples of suitable triglycerides as are flaxseed andalmond oils, based on their compositions. These oils have unsaturationprofiles, illustrated in FIGS. 4A and 4B, that set them apart from othercommon dietary fats. “OTHER” in these figures refers to: corn, peanut,sesame, walnut, soybean, sunflower, grape and safflower oils. In FIG. 4Bthe odd:even ratio is the ratio of unsaturation from mono- andtri-unsaturated fatty acids to that from di-unsaturated acids. It shouldbe noted that unless they are conjugated, di-unsaturated fatty acids donot provide the same membrane disordering potential as mono- andtri-unsaturated acyl groups. Although it produces a modulation of BAC,corn oil that is rich in C18:2 linoleic acid less effective at BAC peakreduction than a mixture of corn oil with olive oil. (C18:2 linoleicacid that has an 18-carbon chain and two cis double bonds.) Exemplarytriglyceride mixtures in some embodiments of this invention are high inunsaturation and/or have a high proportion of mono- and tri-unsaturatedacids in their unsaturated fatty acids. It is noted that fish and algaloils are not common dietary fats, and their high content of the highlypolyunsaturated fatty acids EPA and DHA (with 5 and 6 double bonds,respectively) produce significant bilayer disorder in phospholipidbilayers in which they are incorporated.

Example 6 pH of Lecithin Composition

In order to maintain a dispersed state on exposure to stomach acid, thecompositions according to embodiments of the invention should preferablyremain at a pH above the pK of the charged phospholipids of theirconstituent lecithin (e.g., pK of 2.5-3.0). The amount and acidity ofgastric fluid present in the human stomach varies widely. However, useof a suitable physiologically acceptable food acidulant (such as thoseadded for flavor profile and pH adjustment) can provide sufficientbuffer capacity to maintain stomach pH in an acceptable range. There areseveral known suitable acidulants, and concentrations and starting pHsthereof, that can provide this buffer capacity. FIG. 5 shows the BACprofiles for a formulation prepared as described in Example 4 with 2.5 gmixed triglycerides and 3.75 g soy lecithin in each 250 ml. The uppercurves are for a samples containing 2 g citric acid at pH 5.4 or 4.2.The pH 5.4 data are the average of results from samples withtriglyceride compositions of 1:1 corn oil:canola oil and 1:1 cornoil:olive oil. All other data are averages of duplicate 1:1 cornoil:olive oil triglyceride mixture sample results and shows reduced BAClevels below the control study levels of FIG. 3, but not as low as thetest formulation data. With all other component proportions maintainedconstant, the lower curve demonstrates the effect of doubling the citricacid content (to 4 g) to a level where exposure of the HLCVs tounacceptably low pH is avoided, and a greater reduction in BAC isobserved.

Example 7 Reduced Alcohol Flushing Syndrome

Inhibition of alcohol uptake may also be monitored, in susceptibleindividuals, by observations of alcohol flushing syndrome. Those with aparticular gene variant, most often of Asian descent, have low levels ofthe aldehyde dehydrogenase enzyme. Thus, alcohol that enters theirbloodstream is metabolized to acetaldehyde which is not efficientlydegraded, and consequently builds up to toxic levels. The toxicity mostobviously manifests as skin flushing and accelerated heart rate. Anadult Asian female with known alcohol flushing syndrome was monitoredfor heart rate, using a fingertip pulse oximeter (Facelake CMS50D+) withdata subsequently downloaded by USB cable to a computer for display andprint out, and for facial appearance using digital photography withimage analysis. In a control study, one half glass (75 ml) of white wine(13 vol. % alcohol) was consumed in three 25 ml aliquots at fifteenminute intervals after which monitoring was continued for one hour. Bothtachycardia (elevated heart rate) and deep red facial flushing wereapparent within 30 minutes of consuming the first aliquot of alcohol. Inthe test study, the procedure was repeated approximately 20 minutesafter consuming the triglyceride formulation of Example 3. FIG. 6 showsthe heart rate traces from the control and test procedures. Thealcohol-induced elevation of heart rate is clearly seen for thissusceptible individual but this tachycardia is effectively eliminated inthe test case when the triglyceride formulation is consumed before thewine. In addition, photographs were taken full-face without flash andstored as JPEG images that were rendered in grayscale and analyzed forintensity using Image-J, a public domain Java image-processing programbased on United States National Institutes of Health image analysissoftware. The image intensity profile was obtained left to right along ahorizontal line starting and finishing in the subject's hair andcrossing the tip of the nose (lines shown in FIG. 7A). The hair providesa low intensity region at each extreme of the profile and the tip of thesubject's nose (very reflective in the images) is a high intensitymarker. To adjust for variations in distance from the camera andpositioning in the field of view, profile horizontal scales werenormalized to the same width by linear scaling and images wereregistered (i.e. left or right shifted) to align the shadows at the edgeof the nostrils on either side of the nose. Shown in FIG. 7B, theessentially overlapping upper traces correspond to images from beforethe consumption of alcohol (CONTROL) and after consumption when theformulation of the invention was consumed beforehand (FORMULA). In thealcohol consumption case, facial flushing in which the skin colorchanges from a light flesh tone to a dark red appearance is clearly seenas a significant decrease in intensity in the two portions of theprofile corresponding to the cheeks (ALCOHOL).

Example 8 Pharmacokinetics (PK)-Bioavailability

Following an overnight fast, a male volunteer consumed 1.2 g of EPA+DHAformulated as 4 g 18:12 fish oil triglycerides (18% EPA and 12% DHA)with 6 g lecithin and prepared as described in Example 1. Elevation ofplasma levels of the EPA and DHA omega-3 fatty acids was subsequentlymonitored at 15-30 minute intervals. The fatty acids were analyzed bygas chromatography-mass spectrometry (GCMS) following plasma extraction,triglyceride acid hydrolysis, derivatization with pentafluorobenzylbromide (PFBBr) and further extraction, An internal free fatty acidstandard was used in the assays. Blood plasma levels are shown in FIG.8, with the three-point moving average shown as a solid line. Forcomparison, FIG. 8 also illustrates the data for a prescription omega-3gel cap product (4 g total triglyceride dose, 3.1 g DHA+EPA; Lovaza)taken with a low fat diet. Even at a 2.5 times lower dose, thetriglyceride-lecithin formulation produces a notably greater omega-3plasma level enhancement than the gel cap. (The control omega-3 gel capwas disclosed in Davidson et al., Poster Presentation DALM XVIIInternational Symposium, Doha, Qater, March 2011.)

While the present invention has been illustrated and described withreference to certain exemplary embodiments, those of ordinary skill inthe art will understand that various modifications and changes may bemade to the described embodiments without departing from the spirit andscope of the present invention, as defined in the following claims.

1. A composition, comprising a stable homogeneous dispersion,comprising: a vesicle having a membrane and an aqueous phase, thevesicle comprising: lecithin; and a triglyceride source dispersed in thelecithin; and conditioned water.
 2. The composition of claim 1, whereinthe lecithin has a phosphatidylcholine content of about 80 w/w % orless.
 3. The composition of claim 1, wherein the vesicle has avolume-weighted mean diameter of about 500 nm or less.
 4. Thecomposition of claim 1, wherein the triglyceride source has an overallunsaturated fatty acid to saturated fatty acid ratio of at least 4:1 byweight.
 5. The composition of claim 1, wherein the triglyceride sourcehas a ratio of the sum of mono-unsaturated fatty acids andtri-unsaturated fatty acids to di-unsaturated fatty acids of at least1:1.
 6. The composition of claim 1, wherein the triglyceride source hasan average oleic acid content of at least 40% by weight based on thetotal weight of fatty acids in the triglyceride source.
 7. Thecomposition of claim 1, wherein the triglyceride source comprises oliveoil, and/or, canola oil, and/or almond oil, and/or flaxseed oil, and/orcombinations thereof.
 8. The composition of claim 7, wherein thetriglyceride source is at most 50% by weight based on the total weightof the lecithin and the triglyceride source.
 9. The composition of claim8, wherein the triglyceride source is a mixture of corn oil and oliveoil.
 10. The composition of claim 1, further comprising an acidulantbuffer.
 11. The composition of claim 10, wherein the acidulant buffer ispresent in a molar ratio of acidulant buffer to lecithin of about 0.1:1to about 5:1.
 12. The composition of claim 10, wherein the molar ratioof acidulant buffer to lecithin is at least 5:1.
 13. The composition ofclaim 1, wherein the vesicle further comprises a lipophilic agentdispersed therein.
 14. The composition of claims 1, further comprising awater soluble agent.
 15. The composition of claim 13 wherein thetriglyceride source comprises carbon chain lengths of less than 14carbons and/or saturated fatty acids.
 16. The composition of claim 14,wherein the water soluble agent is an appetite suppressant.
 17. Thecomposition of claim 16, wherein the appetite suppressant is a solublefiber and/or a phytochemical, and/or a combination thereof.
 18. A methodfor suppressing an appetite of a human or animal, comprising:administering the composition of claim 1 to the human or animal.
 19. Acomposition, comprising a stable homogenous dispersion, comprising: avesicle having a membrane and an aqueous phase, the vesicle comprising:lecithin; and at least one fatty acid dispersed in the lecithin; andconditioned water.
 20. The composition of claim 19, wherein the at leastone fatty acid is an omega-3 fatty acid or a mixture of omega-3 fattyacids.
 21. The composition of claim 19, wherein the at least one fattyacid is eicosapentaenoic acid (EPA) and/or docosahexaenoic acid (DHA).22. The composition of claim 1, further comprising an active agent. 23.A method of delivering an active agent to the small intestine of a humanor animal, comprising: administering the composition of claim 22 to thehuman or animal.
 24. A method of delivering an active agent to thebloodstream of a human or animal, comprising: administering thecomposition of claim 22 to the human or animal.
 24. (canceled)
 25. Amethod of attenuating facial flushing and/or an increase in heart rateof a human or animal caused by consumption of alcohol, comprising:administering the composition of claim 1 to the human or animal.
 26. Themethod of claim 23, wherein the active agent is a plant sterol or atleast one lipophilic compound.